Cystic Fibrosis (CF) is the most common lethal genetic disorder in Caucasian populations and is caused by defects in the cystic fibrosis conductance regulator (CFTR) chloride channel. CF is a multi-organ disease affecting the lung, pancreas, liver, intestine, and gallbladder. Cystic fibrosis related diabetes (CFRD) is the most common significant complication of CF and is well known to be associated with increased morbidity and mortality. CFRD, which is pathophysiologically distinct from type 1 and type 2 diabetes, significantly impacts the nutritional and pulmonary health of CF patients. The incidence of CFRD increases with age, but the underpinnings of the disease likely occur early in life. Glycemic abnormalities are not uncommon in children with CF and the 13% of CF children 6-10 years of age that have abnormal glycemic status are at extraordinarily high risk for development of diabetes within the next few years. Thus, early detection of CF patients at risk for developing CFRD is critical to improved clinical care. Understanding the early pathophysiology of CFRD has been hampered in the past by lack of an animal model with a clinical picture similar to that in humans with CF. However, the University of Iowa has developed a novel CFTR-knockout ferret animal model that develops a clinical course of lung and pancreatic disease as seen in human CF patients, including early glycemic abnormalities and progression to glucose intolerance. This CF ferret model, in conjunction with human studies in CF infants and children, will be used by this R24 to clarify pathophysiologic mechanisms of endocrine pancreas dysfunction observed in both CF humans and ferret. This application will define both pancreatic-intrinsic and -extrinsic factors that influence insulin secretion by the Bet-cell in CF, with a focus on (i) CFTR-dependent intrinsic functions within the islet, (ii) CFTR-dependent exocrine pancreas contributions to islet dysfunction, and (iii) CFTR-dependent alterations in the intestine that influence enteroinsular axis hormones. This R24 has brought together experts in areas of islet and Beta-cell ion channel physiology pertaining to insulin secretion (University of Chicago), diabetes and pancreatitis in CF animal models (University of Iowa), clinical studies in CFRD patients (University of Minnesota), and bacteriology (Iowa State University), to tackle the challenging question of how defects in CFTR lead to the development of diabetes. Although the application focuses on early disease pathophysiology, it also has great potential for identifying blood biomarkers for early diagnosis of patients at risk for CFRD.